A Two Steps Phase I Trial of Pazopanib or Pemetrexed in Combination With Crizotinib Followed by the Triplet, Crizotinib Plus Pazopanib Plus Pemetrexed in Patients With Advanced Malignancies (2011-1142)Summary

Using a combination of drugs may be more effective than using one drug alone for treating advanced breast cancer. Crizotinib (Xalkori) blocks a protein called ALK, which is involved in cancer cell growth and survival. It is approved to treat some types of non-small cell lung cancer. Pazopanib (Votrient) blocks the growth of blood vessels that supply nutrients needed for tumor growth. It is approved for the treatment of advanced kidney cancer. Pemetrexed (Alimta) blocks proteins that may cause tumors to grow. It is approved for the treatment of non-small cell lung cancer. The goal of this trial is to identify the highest tolerable dose and to study the safety of the combination of crizotinib and pazopanib; crizotinib and pemetrexed; and crizotinib, pazopanib and pemetrexed in patients with advanced breast cancer. Patients with other types of advanced cancer are also being enrolled in this study.
This is a Phase I trial

Purpose The goal of this clinical research study is to find the highest tolerable dose of the combination of Xalkori (crizotinib) either with Votrient (pazopanib) or Alimta (pemetrexed) or of the combination of 3 study drugs that can be given to patients with advanced cancer. The safety of these drug combinations will also be studied.
Crizotinib is designed to block a protein called ALK, which is involved in cancer cell growth and survival.
Pazopanib is designed to block the growth of blood vessels that supply nutrients needed for tumor growth. This may prevent or slow the growth of cancer cells.
Pemetrexed is designed to block proteins that may cause tumors to grow.

Arms Assigned Interventions Experimental: Crizotinib (Xalkori) + Pazopanib Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug.
Dose Expansion Group: MTD from Phase 1.
Starting Dose for Pazopanib: 200 mg by mouth daily in a 21 day cycle.
Dose Expansion Group: MTD from Phase 1.

Drug: Crizotinib (Xalkori) Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug.
Dose Expansion Group: MTD from Phase 1.

Other Name: GW786034
Experimental: Crizotinib (Xalkori) + Pemetrexed Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug.
Dose Expansion Group: MTD from Phase 1.
Starting dose for Pemetrexed: 200 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle.
Dose Expansion Group: MTD from Phase 1.

Drug: Crizotinib (Xalkori) Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug.
Dose Expansion Group: MTD from Phase 1.

Other Names:

PF-02341066

Xalkori

Drug: Pemetrexed Starting dose for Pemetrexed: 200 mg/m2 by vein on Day 1 of a 21 day cycle.
Expansion group starting dose: MTD from Phase 1.
Starting dose for Pemetrexed: 400 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle.

Other Names:

LY231514

Alimta

MTA

Multitargeted Antifolate

NSC-698037

Experimental: Pazopanib + Pemetrexed Starting dose for Pazopanib: 200 mg by mouth daily in a 21 day cycle.
Expansion group starting dose: MTD from Phase 1.
Starting dose for Pemetrexed: 200 mg/m2 by vein on Day 1 of a 21 day cycle.
Expansion group starting dose: MTD from Phase 1.

Other Name: GW786034
Drug: Pemetrexed Starting dose for Pemetrexed: 200 mg/m2 by vein on Day 1 of a 21 day cycle.
Expansion group starting dose: MTD from Phase 1.
Starting dose for Pemetrexed: 400 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle.

Other Names:

LY231514

Alimta

MTA

Multitargeted Antifolate

NSC-698037

Experimental: Crizotinib (Xalkori) + Pazopanib + Pemetrexed Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug.
Dose Expansion Group: MTD from Phase 1.
Starting Dose for Pazopanib: 200 mg by mouth daily in a 21 day cycle.
Dose Expansion Group: MTD from Phase 1.
Starting dose for Pemetrexed: 400 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle.
Dose Expansion Group: MTD from Phase 1.

Drug: Crizotinib (Xalkori) Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug.
Dose Expansion Group: MTD from Phase 1.

Other Name: GW786034
Drug: Pemetrexed Starting dose for Pemetrexed: 200 mg/m2 by vein on Day 1 of a 21 day cycle.
Expansion group starting dose: MTD from Phase 1.
Starting dose for Pemetrexed: 400 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle.

Creatinine Clearance: The standard Cockcroft and Gault formula must be used to calculate CrCl for enrollment or dosing. Also include in the pre-treatment or baseline text portion of the protocol, the 'On Study Evaluations or During Treatment' for every Pemetrexed treatment day, and also capture in the study Schedule of Events. No dosage adjustment is needed in patients with creatinine clearance > 45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, Pemetrexed should not be administered to patients whose creatinine clearance is <45 mL/min.

For pemetrexed arms: The ability to interrupt NSAIDs 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed.

The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol for all pemetrexed arms.

Medical and/or psychiatric problems of sufficient severity to limit full compliance with the study or expose patients to undue risk.

Known anaphylactic or severe hypersensitivity to study drugs or their analogs.

Patient has failed to recover from any prior surgery within 4 weeks of study entry.

Patient is pregnant or lactating.

Patient has had any treatment specific for tumor control within 3 weeks of dosing with investigational drugs and cytotoxic agents, or within 2 weeks of cytotoxic agent given weekly, or within 6 weeks of nitrosoureas or mitomycin C, or within 5 half-lives of biological targeted agents with half-lives and pharmacodynamic effects lasting less than 5 days (that includes, but is not limited to, erlotinib, sorafenib, sunitinib, bortezomib, and other similar agents).

Patient has any signs of intestinal obstruction.

Patient is not able to swallow oral medication.

Patients receiving whole brain radiation within 14 days prior to the first dose of study drugs will be excluded. NOTE: Patients receiving palliative radiation (other than whole brain) before or during treatment may still be eligible as long as there are evaluable lesions that are not being irradiated.

Pemetrexed arms only: Presence of third space fluid which cannot be controlled by drainage.

Additional Exclusions for the 3 pazopanib containing arms (Crizotinib plus Pazopanib) and (Pazopanib plus Pemetrexed) and (Crizotinib plus Pazopanib plus Pemetrexed). 1. History of stroke or transient ischemic attack within 6 months prior to study enrollment. 2. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment. 3. Urine for proteinuria > or = 2+ (patients discovered to have > or = 2+ proteinuria on urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate < or = 1g of protein in 24 hours to be eligible).

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01548144